United States Patent (19) 11, 3,928,358 Renth et al. (45) Dec. 23, 1975

54 PPERAZINE DERVATIVES R2 S (75) Inventors: Ernst Otto Renth; Kurt Schromm; H - CH - N' YN , Anton Mentrup, all of Ingelheim am f V. A A. Rhein; Peter Danneberg, OR CH3 3-1 Ockenheim, all of Germany 73) Assignee: Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany 22 Filed: May 15, 1974 wherein (21) Appl. No.: 469,944 A is trimethylene, tetramethylene, trimethyleneoxy, methylenedioxy, ethylenedioxy or, together with the adjacent benzene ring, g-naphthyl, 30 Foreign Application Priority Data R is alkyl of one to four carbon atoms, alkanoyl of May 21, 1973 Germany...... 2325633 two to seven carbon atoms, (alkyl of one to four carbon atoms)-carbamoyl or phenyl-carbamoyl, (52) U.S. Cl...... 260/268 BC; 424/250 R is hydrogen, alkyl of one to four carbon atoms, 51 int. Cl...... CO7D 295/12 alkoxy of one to four carbon atoms, halogen or 58 Field of Search...... 260/268 BC, 268 PH trifluoromethyl, Rs is hydrogen, alkyl of one to four carbon atoms, (56) References Cited alkoxy of one to four carbon atoms or halogen, UNITED STATES PATENTS and 3,729,474 4/1973 Mentrup et al...... 260/268 BC R. and Ra, together with each other and the carbon 3,810,897 5/1974 Phillipe...... 260/268 BC attached,atoms of formthe thephenyl benzene ring ring,to which they are Primary Examiner-Donald G. Daus and non-toxic, pharmacologically acceptable acid ad Assistant Examiner-Jose Tovar dition salts thereof; the compounds as well as the salts Attorney, Agent, or Firm-Hammond & Littell are useful as neuroleptics, analgesics, spasmolytics, 57 ABSTRACT broncholytics, hypotensives and anti-cholesteremics. Compounds of the formula 4 Claims, No Drawings 3,928,358 2 PPERAZINE DERVATIVES wherein A, R, and Ra have the same meanings as in This invention relates to novel derivatives of pipera formula I, with a compound which is suitable for intro zine and non-toxic acid addition salts thereof, as well as duction of the particular R-substituent which is de sired. to a method of preparing these compounds. For example, if R in formula 1 is to be alkanoyl, the More particularly, the present invention relates to a alcohol of the formula II is reacted with the corre novel class of piperazine derivatives represented by the sponding acid anhydride or alkanoyl halide; if R is to formula be a carbamoyl group, the alcohol is reacted with the corresponding isocyanate; and if R is to be alkyl, the CH - CH - N () alcohol is reacted with the corresponding diazoalkane in the presence of borontrifluoride etherate, or with O-( ) another alkylating agent, such as the corresponding ba, l, R3 alkyl halide after conversion of the alcohol into the (I) sodium alcoholate with the aid of sodium hydride or 5 sodium amide. If the erythro- or threo-form of the alcohol of the wherein formula II is used as the starting compound in the A is trimethylene, tetramethylene, trimethyleneoxy, above reactions, the end product of the formula I is also methylenedioxy, ethylenedioxy or, together with obtained in the erythro- or threo-form, respectively. the adjacent benzene ring, g-naphthyl, In those instances where the above reactions yield a R is alkyl of one to four carbon atoms, alkanoyl of racemic mixture of a compound of the formula I, the two to seven carbon atoms, (alkyl of one to four same may be separated into its optically active compo carbon atoms)-carbamoyl or phenyl-carbamoyl, nents by conventional methods, such as by forming R is hydrogen, alkyl of one to four carbon atoms, diastereomers with suitable optically active acids, and alkoxy of one to four carbon atoms, halogen or 25 separating them by fractional crystallization. trifluoromethyl, The compounds embraced by formula I are organic R is hydrogen, alkyl of one to four carbon atoms, bases and therefore form acid addition salts with inor alkoxy of one to four carbon atoms or halogen, and ganic or organic acids. Examples of non-toxic, pharma R and R, together with each other and the carbon cologically acceptable acid addition salts are those atoms of the phenyl ring to which they are at formed with hydrochloric acid, hydrobromic acid, sul tached, form the benzene ring, furic acid, phosphoric acid, acetic acid, propionic acid, and non-toxic, pharmacologically acceptable acid addi maleic acid, tartaric acid, citric acid, 8-chlorotheophyl tion salts thereof. line or the like. A sub-genus thereunder is constituted by compounds The starting compounds of the formula II may be of the formula wherein 35 prepared by first reacting a bromo-ketone of the for A is methylenedioxy, ethylenedioxy or trimethy mula leneoxy, R is alkanoyl of two to seven carbon atoms, (alkyl of one to four carbon atoms)-carbamoyl or phenyl CH3 carbamoyl, CO-CH-Br (III) R is hydrogen, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms or halogen, Ra is hydrogen or methyl, and R and R, together with each other and the carbon atoms of the phenyl ring to which they are at 45 tached, form the benzene ring, wherein A has the same meanings as in formula I, with and their non-toxic, pharmacologically acceptable acid a piperazine derivative of the formula addition salts. Another sub-genus thereunder is constituted by com R2 a pounds of the formula I wherein HN N (IV) A is methylenedioxy of ethylenedioxy, \-/ R is acetyl, propionyl or butyryl, 31 R is hydrogen, methyl or chlorine, R is hydrogen or methyl, and R and Ra, together with each other and the carbon 55 wherein R and Ra have the same meanings as in for atoms of the phenyl ring to which they are at mula I, to form a piperazino-ketone of the formula tached, form the benzene ring, and their non-toxic, pharmacologically acceptable acid addition salts. CH R The compounds embraced by formula I may be pre 2 N pared by reacting an alcohol of the formula CO-CH-N -(C N-/ R3 W

65 (v) (II) wherein A. R. and R. have the meanings previously defined. 3,928,358 3 4 An erythr-alcohol of the formula I (Y-form) is al. 7.4 gm (20 millimols) of the end product obtained (btained by catalytic reduction of ketone of the for in (c) were admixed with 50 ml of acetic acid anhy mula V in the presence of Raney nickel, platinum or dride, and the mixture was refluxed for 1 hour, while palladium. stirring. Thereafter, the reaction mixture was evapo A threo-alcohol of the formula II (Z-form) is ob rated to dryness in vacuo, the residue was dissolved in tained by reduction of a ketone of the formula V with methanol, and the calculated amount of concentrated a complex hydridc. such as lithium borohydride, so hydrochlorie acid was added to the solution. The mix dium borohydride, potassium borohydride, lithium ture was then diluted with water ( ; ), stirred for 3 () aluminum hydride or sodium bis-(2-methoxy-ethoxy)- minutes, vacuum-filtered, and the filter cake was re aluminum hydride, or under the conditions of the () crystallized from ethanol, yielding 75 gm (8.4% of the Meerwein-Ponndorf-Verley reduction. ory) of the compound of the formula The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be under stood, however, that the invention is not limited solely 5 H3 to the particular examples given below. -CH-CH-N h() o HCl EXAMPLE 1 \-/ Erythro-1-(1,4'-benzodioxan-6'-yl)-2- N'-(o-tolyl)- Chs piperazino-propanol-O-acetate hydrochloride C=O a. 6-(2'-Bromo-propionyl)-1,4-benzodioxan 417 gm (2.18 mol) of 6-propionyl-1,4-benzodioxan bi, were dissolved in 1.5 liters of ether, the solution was warmed to 30°C, 1 12 ml (2.8 mol) of bromine were which had a melting point of 232-235°C. slowly added to the warn solution, and the resulting EXAMPLE 2 mixture was stirred for 30 minutes. Thereafter, the solvent was distilled off in vacuo, the residue was Threo-l-( l',4'-benzodioxan-6'-yl)-2- N'-(o-tolyl)- stirred with 1 liter of methanol, the mixture was cooled piperazino-propanol-O-acetate hydrochloride and vacuum-filtered. and the filter cake was dried. 49 (i. Threo-1-( l',4'-benzodioxan-6'-yl)-2-N'-(o- gm (83% of theory) of 6-(2'-bromo-propionyl)-1,4- 3) tolyl)-piperazino-propanol benzodioxan, m.p. 91-92°C, were obtained. 36.6 gm (0. mol) of 3',4'-ethylenedioxy-2-N'-(o- b. 3',4'-Ethylenedioxy-2- N'-(o-tolyl)-piperazino tolyl)-piperazino-propiophenone, m.p. 116°C (pre propiophenone dihydrochloride pared as described in Example lb), were dissolved in 90 gm (().33 mol) of the bromo-ketone obtained in 35 l()() ml of ethanol and, while maintaining the solution (a) were dissolved in 1000 ml of benzene, and then .5 at 10-15°C, 1.9 gm (().05 mol) of sodium borohydride ml of isopropylamine and subsequently 16 gm (0.66 were added thereto. The resulting mixture was stirred mol) of N-(o-tolyl)-piperazine were added to the solu for two hours at room temperature and thereafter tion. The resulting mixture was stirred at room temper poured into water, and the aqueous mixture was ex ature for 24 hours, then cooled, and the precipitated tracted with ether. The ethereal extract was evaporated N-(o-tolyl)-piperazine hydrobromide was separated by in vacuo, and the residue was recrystallized from meth vacuum filtration. The benzene was distilled out of the anol, yielding 21 gm (57% of theory) of the above filtrate in vacuo, the residue was taken up in 200 ml of named threoalcohol, m.p. 109-1 l l C. methanol, and the solution was acidified with ethereal b. 18.4 gm (0.05 mol) of the threo-alcohol obtained hydrochloric acid. 600 ml of methyl isobutyl ketone 45 in (a) were admixed with 100 ml of acetic acid anhy were then added, and the mixture was heated at 80°C, dride, and the mixture was refluxed for 1 hour. There while distilling off the major amount of the ether in a after, the reaction mixture was cvaporated in vacuo, descending condenser tube, until a clear solution was the residue was dissolved in methanol, and the calcu formed. The solution was allowed to cool, and the lated amount of concentrated hydrochloric acid was precipitate formed thereby was collected by vacuum added to the solution. The mixture was then diluted filtration and dried, yielding 97 gm (67% of theory) of with water, stirred until crystallization was complete 3',4'-ethylenedioxy-2-N'-(o-tolyl)-piperazino-propi and then vacuum-filtered, and the filter cake was re ophenone dihydrochloride. crystallized from methanol. 15.3 gm (68% of theory) of C. Erythro-1-(1,4'-benzodioxan-6'-yl)-2-N'-(o- threo-1-(l',4'-benzodioxan-6'-yl)-2-N'-(o-tolyl)- tolyl)-piperazino)-propanol 55 piperazino-propanol-O-acetate hydrochloride, m.p. 22.0gm (0.05 mol) of 3',4'-ethylenedioxy-2-N'-(o- 218-220C, were obtained. tolyl)-piperazino)-propiophenone dihydrochloride were suspended in 200 ml of water, and the suspension EXAMPLE 3 was made weakly alkaline by addition of dilute ammo Erythro-1-(l',4'-benzodioxan-6'-yl)-2-N'-(o-tolyl)- nia. The mixture was then extracted with ethyl acetate, 6) piperazino-propanol-O-enanthate hydrochloride the extract was diluted with methanol ( ): T ), and after 9.2 gm (25 millimols) of erythro-1-(i',4'-benzodiox addition of Raney nickel the solution was hydrogenated an-6'-yl)-2-N'-(o-tolyl)-piperazino-propanol were until the calculated amount of hydrogen had been ab dissolved in 50 ml of acetonitrile, 3.7gm (25 millimols) sorbed. Thereafter, the catalyst was vacuum-filtered 65 of enanthic acid chloride were added to the solution, off, the solvent was distilled out of the filtrate in vacuo, and the mixture was refluxed for 45 minutes. Thereaf and the residue was recrystallized from ethanol, yield ter, the reaction mixture was cooled, poured into wa ing 9 gm (5% of theory) of erythro-1-( t '4'-benzodi ter, and the aqueous mixture was extracted with ethyl oxan-6'-yl)-2- N'-(o-tolyl)-piperazino-propanol, m.p. acetate. The extract solution was evaporated in vacuo, 127°-28°C. the residue was dissolved in ethanol, and the solution 3,928,358 S 6 was made weakly acid with ethereal hydrochloric acid. 4.0 gm (10 millimols) of erythro-1-(chroman-6'-yl)- The acidic mixture was cooled. Vacuum-filtered, and 2- N'-(o-naphthyl)-piperazino-propanol were dis the filter cake was recrystallized from isopropanol, solved in 100 ml of ether, and, while keeping the tem yielding 6.0gm (46.5% of theory) of the hydrochloride perature of the solution below 20°C, 1.4 gm (10 milli named in the heading, which had a melting point of mols) of borontrifluoride etherate were added. Subse 215-21.6°C. quently, an ethereal 0.1 N diazomethane solution was slowly added until the mixture remained yellow. The EXAMPLE 4 resulting mixture was then allowed to stand overnight, Erythro-1-(3',4'-methylenedioxy-phenyl)-2-N'-(op the solvent was distilled off in vacuo, the residue was xylyl)-piperazino-propanol-O-butyrate hydrochloride 10 taken up in methanol, and the solution was weakly Erythro-1-(3',4'-methylenedioxy-phenyl)-2-N'- acidified with dilute hydrochloric acid. The crystalline (op-xylyl)-piperazinol-propanol, m.p. 131-132C, substance precipitated thereby was collected by vac was prepared, starting from 3.4-methylenedioxy-propi uum filtration and recrystallized from methanol in the ophenone in a manner analogous to that described in presence of charcoal, yielding 2.3 gm (55% of theory) Example (a)-(c). t5 of the compound of the formula 2.4 gm (6.5 millimols) of the crythro-alcohol thus obtained were admixed with 30 ml of butyric acid an hydride, and the mixture was stirred for 1 hour at 140-150°C. Thereafter, the solvent was distilled off in ill-ill-, - ( ) vacuo, the residue was dissolved in ethanol, and the 2) CH3 K) HCl solution was admixed with dilute hydrochloric acid until it was weakly acid. The precipitate formed CH3 thereby was collected by vacuum filtration and recrys tallized from ethanol, yielding 2.0gm (65% of theory) which had a melting point of 213-215°C. of the compound of the formula 25 EXAMPLE 7 Erythro-1-(4',5'-inelanyl)-2-(N'-(o-naphthyl)- - H3 piperazinopropy n-butyl ether hydrochloride 7.6 gm (20 millimols) of erythro-1-(4',5'-indanyl)-2- N'-(a-naphthyl)-piperazino)-propanol, m.p. CH3 42-144C, were dissolved in 100 ml of absolute di glyme, and, while stirring, 1.0 gm of 50% sodium hy Koro-5-)-.O dride was added to the solution, and the mixture was stirred for about 1 hour at 50°C. After the evolution of 35 gas had ceased, the reaction solution was cooled, and then 3.4 gn (25 millimols) of n-butyl bromide were which had a melting point of 227-228C. added dropwise. The resulting mixture was refluxed for EXAMPLE 5 2 hours and then slowly poured into 200 ml of ice Erythro-N-(n-butyl)-1-(1,4'-benzodioxan-6'-yl)-2- 4) water. The aqueous mixture was extracted with ethyl 4'-(a-naphthyl)-1'-piperazinol-propyl-urethane acetate, the extract was evaporated to dryness in vacuo, the residue was taken up in methanol, and the hydrochloride solution was acidified with dilute hydrochloric acid. 1.5gm (0.37 millimols) of erythro-1-(i',4'-benzodi The precipitate formed thereby was collected by vac oxan-6'-yl)-2-4'-(a-naphthyl)-1'-piperazino 45 uum filtration and recrystallized from isopropanol, propanol, m.p. 132-133°C, were dissolved in 30 ml of yielding 3.8 gm (43% of theory) of the compound of benzene, and 0.4gn of n-butyl-isocyanate were added the formula to the solution. The mixture was stirred for hour at 70°C, then cooled, and the solvent was distilled off in vacuo. The residue was dissolved in ethanol, the solu HaCH- N tion was made weakly acid with 2N hydrochloric acid, S and the precipitate formed thereby was collected by vacuum filtration and recrystallized from isopropanol, ?o bits 8. K) a HC yielding 1.0 gm (50% of theory) of the compound pf. the formula i.. 5S which had a melting point of 268-269°C. EXAMPLE 8 -CH-C- Te ( ) HCl Using a procedure analogous to that described in 60 Example 1 (d), erythro-1-(chroman-6'-yl)-2-N'-(a- OC Ofl-l-ly Chi naphthyl)-piperazino-propanol-O-acetate hydrochlo i 3 ( ) ride, m.p. 224°C, of the formula which had a melting point of 87-88°C. 65 f 1.03 HC EXAMPLE 6 OCCO Erythro-1-(chroman-6'-yl)-2-N'-(o-naphthyl)- o piperazino-propyl methyl ether hydrochloride CH3 3,928,358 7. was prepared from erythro-1-(chroman-6'-yl)-2-N'- (a-naphthyl)-piperuzino-propanol and acetic acid anhydride. HC EXAMPLE 9 Using a procedure analogous to that described in Example 1(d), erythro-1-(3',4'-methylenedioxy phenyl)-2-N'-(o-naphthyl)-piperazinol-propanol O-acetate, hydrochloride, m.p. 242°C, of the formula () was prepared from erythro-1-(l',4'-benzodioxan-6'- yl)-2-N'-(o-tolyl)-piperazino-propanol and phenyl /N-1s-2H-CH-. j-K) isocyanate. m H20, \- / HC EXAMPLE 3 5 Using a procedure analogous to that described in or is ( ) Example 1 (d), erythro-1-(3',4'-methylenedioxy phenyl)-2-N'-(o-tolyl)-piperazino-propanol-O-ace H3 tate hydrochloride, m.p. 234-235°C, of the formula was prepared from erythro-1-(3',4'-methylenedioxy phenyl)-2-N'-(a-naphthyl)-piperazino-propanol and acetic acid anhydride. /- He 1. HC EXAMPLE O No Using a procedure analogous to that described in CH3 CH3 Example 4, erythro-1-(3',4'-methylenedioxy-phenyl)- OsC 2- N'-(o,p-xylyl)-piperuzino-propanol-O-butyrate hy drochloride, m.p. 227-228°C, of the formula h; 3) was prepared from erythro-1-(3',4'-methylenedioxy :-c1 O -:-G"-itA \n- (\ \) -CH phenyl)-2-N'-(o-tolyl)-piperazino)-propanol and --. N Y W aar- al acetic acid anhydride. () C Cl C. C:- 35 EXAMPLE 14 Using a procedure analogous to that described in of - Example 5, erythro-N-methyl-1-(g-naphthyl)-2-N'- -f- - phenyl-piperazino-propyl-urethane hydrochloride, mp. 18 °-182'C, of the formula was prepared from erythro-1-(3',4'-methylenedioxy phenyl)-2- N'-(()p-xylyl)-piperazino-propanol and butyric acid anhydride. i? Y-/ \ EXAMPLE 45 OriCC... 1 C Hs a Using a procedure analogous to that described in Example 3, erythro-1-( l',4'-benzodioxan-6'-yl)-2-N'- (o-tolyl)-piperazino-propanol-O-pentanoate hydro chloride, m.p. 228-229°C, of the formula 5. was prepared from erythro-1-(p-naphthyl)-2-N'-phe O -CH-CH-N N nyl-piperazino-propanol and methyl-isocyanate. s l, \-/ HC EXAMPLE 5 CH3 CH3 55 Using a procedure analogous to that described in OsC Example (d), erythro-1-(3',4'-methylenedioxy phenyl)-2-N'-(o-chloro-phenyl)-piperazino propanol-O-acetate hydrochloride, m.p. 219–22°C. of the formula was prepared from crythro-1-(l',4'-benzodioxan-6'- yl)-2-N'-(o-tolyl)-piperazino-propanol and penta noic acid chloride. ---O-\-/ • HCl EXAMPLE 2 65 Using a procedure analogous to that described in scot. C Example 5, crythro-N-phenyl-1-( l',4'-benzodioxan-6'- yl)-2-N'-(o-tolyl)-piperazino-propyl-urethane hydro O chloride, m.p. 235-237°C, of the formula CH3 3,928,358 9 10 was prepared from erythro-1-(3',4'-methylenedioxy soluble starch, and the moist mass is granulated phenyl)-2-(N'-(o-chloro-phenyl)-piperazino through a fine-mesh screen. The granulate is dried and propanol and acetic acid anhydride. admixed with the remainder of the excipients, and the composition is compressed into 250 mgm-tablets in a EXAMPLE 6 conventional tablet making machine. Each tablet con Using a procedure analogous to that described in tains 30 mgm of the piperazine derivative and is an oral Example 3, erythro-1-(l',4'-benzodioxan-6'-yl)-2-N'- dosage unit composition with effective neuroleptic (m-trifluoromethyl-phenyl)-piperazinol-propanol-O- action. propionate hydrochloride, m.p. 202-205°C, of the formula () EXAMPLE 8 Coated pills The pill core composition is compounded from the following ingredients: -h-i- \/N e HC O CH3 5 Erythro-1-( '4'-benzodioxan-6'-yl)- CF3 2- N'-(o-tolyl)-piperavino Os propanol-O-acetate hydrochloride 50 parts actose 5th parts Cyrn starch 70 parts Sec. calcium phosphatur 5() parts 2) Magnesium stearate 3 parts was prepared from erythro-1-(1,4'-benzodioxan-6'- a- Schluhle stiruch 3 parts yl)-2-N'-(m-trifluoromethyl-phenyl-piperazino Collicial silicic icic parts - propanol and propionic acid chloride. ontal 25() parts The compounds of the present invention, that is, those embraced by formula I and their non-toxic acid Preparation: addition salts, have useful pharmacodynamic proper 25 The ingredients are compounded in the same manner ties. More particularly, the compounds of this inven as in the preceding example, and the composition is tion exhibit primarily neuroleptic activities and in addi compressed into 250 mgm-pill cores which are subse tion also analgesic, spasmolytic, broncholytic, hypoten quently coated with a thin shell consisting essentially of sive and anti-cholesteremic activities in warm-blooded a mixture of talcum, sugar and gum arabic, and finally animals, such as mice and rats. 30 polished with beeswax. Each coated pill contains 50 For pharmaceutical purposes the compounds accord mgm of the piperazine derivative and is an oral dosage ing to the present invention are administered to warm unit composition with effective neuroleptic action. blooded animals perorally, parenterally or rectally as active ingredients in customary dosage unit composi EXAMPLE 19 tions, that is, compositions in dosage unit form consist 'Tablets with additional spasmolytic ingredient: ing essentially of an inert pharmaceutical carrier and The tablet composition is compounded from the one effective dosage unit of the active ingredient, such following ingredients: as tablets, coated pills, capsules, wafers, powders, solu tions, suspensions, emulsions, syrups, suppositories and 4) Erythro-1-(4-benzodioxan-6'-yl) the like. One effective dosage unit of the compounds 2- N'-(o-tolyl-piperazinol-propanol according to the present invention is from 0.0016 to SSAAFuts hromide EY 1.67 mgm/kg body weight, preferably 0.083 to 0.84 actose 179 parts ngm/kg body weight. &G'Acie acid 2. R The following cxamples illustrate a few pharmaceuti- 45 Polyvinylpyrrollidon 6 parts cal dosage unit compositions comprising a compound Magnesium stcarate 2 parts of the present invention as an active ingredient and Souhle starch - - HE represent the best mode contemplated of putting the Total 450 parts invention into practical use. The parts are parts by weight unless otherwise specified. 5() Preparation: The ingredients are compounded in a manner analo EXAMPLE 1 7 gous to that described in Example l7, and the composi Tablets tion is compressed into 450 mgm-tablets. Each tablet The tablet composition is compounded from the contains 5 mgm of the piperazine derivative and 25 following ingredients: 55 mgm of the scopolammonium compound and is an oral dosage unit composition with effective neuroleptic and spasmolytic actions. stocets hydrochloride 3. E. EXAMPLE 20 S".E, phosphate E. 60 Suppositories with additional analgesic ingredient: Soluble starch 3 parts The suppository composition is compounded from syster's EN the following ingredients: cytal 25() parts 65 2- N'-(o-tolyl)-piperuzino Preparation: propan-O-acetate hydrochloride 30 parts The piperazine derivative is intimately admixed with MS RE a major portion of the inert excipients, the mixture is Suppository base (e.g. cocoa butter) 1796 EA uniformly moistened with an aqueous solution of the Total 1832 parts 3,928,358 12 Preparation: wherein The Suppository base is melted, the other ingredients A is methylenedioxy or ethylenedic Xy, are homogeneously admixed there with, and 1832 R is (alkyl of one to four carbon atoms)-carbamoyl Ingm-portions if the mixture are poured into cooled or phenyl-carbamoyl. Suppository molds and allowed to harlen therein. Each R is hydrogen, alkyl of one to four carbon atoms, Suppository contains 30 mgm of the piperazine deriva alkoxy of one to four carbon atoms, halogen or tive and 10 mgm of metamizol, and is a rectal dosage trifluoromethyl, unit composition with effective neuroleptic, analgesic R. is hydrogen, alkyl of one to four carbon atoms, and antipyretic actions. alkoxy of one to four carbon atoms or halogen, and Analogous results are obtained when any one of the R. and R together with each other and the carbon other piperazine derivatives embraced by formula I or atoms of the phenyl ring to which they are at : nontoxic, pharmacologically acceptable acid addition tached, form the benzene ring, salt thereof is substituted for the particular piperazine or a non-toxic, pharmacologically acceptable acid ad derivative in Examples l7 through 2(). Likewise, the dition salt thereof. amount of active ingredient in these illustrative exam 5. 2. A compound of claim 1, wherein ples may be varied to achieve the dosage unit range set A is methylenedioxy or ethylenedioxy, forth above, and the amounts and nature of the inert R is (alkyl of one to four carbon atoms)-carbamoyl pharmaceutical carrier ingredients may he varied to or phenylcarbamoyl. meet particular requirements. R is hydrogen, alkyl of one to four carbon atoms, While the present invention has been illustrated with () alkoxy of one to four carbon atoms or halogen, the air of certain specific embodiments thereof, it will R is hydrogen or methyl, and be reaclily apparent to others skilled in the art that the R, and R, together with each other and the carbon invention is not limited to these particular embodi atoms of the phenyl ring to which they are at ments, and that various changes and modifications may tached, form the benzene ring, be made without departing from the spirit of the inven 25 or a non-toxic, pharmacologically acceptable acid ad tion or the scope of the appended claims. dition salt thereof. 3. A compound of claim 1, which is erythro-N-(n- We claim: butyl)-1-(1,4'-benzodioxan-6'-yl)-2-4'-(a-napthyl)- 3) 1'-piperazino)-propyl-urethane or a non-toxic, phar 1. A compound of the formula macologically acceptable acid addition salt thereof. 4. A compound of claim 1, which is erythro-N-phe nyl-l-(1,4'-benzodioxan-6'-yl)-2-N'-(o-tolyl)- piperazino-propyl-urethane or a non-toxic, pharmaco 35 logically acceptable acid addition salt thereof. ck sk k : :

45

5)

55